Open AccessGlutamate is an essential mediator in glutamine‐amplified insulin secretion
Author(s) -
Han Guirong,
Takahashi Harumi,
Murao Naoya,
Gheni Ghupurjan,
Yokoi Norihide,
Hamamoto Yoshiyuki,
Asahara Shunichiro,
Seino Yutaka,
Kido Yoshiaki,
Seino Susumu
Publication year - 2021
Publication title -
journal of diabetes investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.089
H-Index - 50
eISSN - 2040-1124
pISSN - 2040-1116
DOI - 10.1111/jdi.13497
Subject(s) - glutamine , medicine , insulin , endocrinology , glutamate receptor , secretion , intracellular , calcium in biology , glutamate dehydrogenase , biology , calcium , biochemistry , amino acid , receptor
Aims/Introduction Glutamine is the most abundant amino acid in the circulation. In this study, we investigated cell signaling in the amplification of insulin secretion by glutamine. Materials and Methods Clonal pancreatic β‐cells MIN6‐K8, wild‐type B6 mouse islets, glutamate dehydrogenase (GDH) knockout clonal β‐cells ( Glud1 KOβCL), and glutamate‐oxaloacetate transaminase 1 (GOT1) knockout clonal β‐cells ( Got1 KOβCL) were studied. Insulin secretion from these cells and islets was examined under various conditions, and intracellular glutamine metabolism was assessed by metabolic flux analysis. Intracellular Ca 2+ concentration ([Ca 2+ ] i ) was also measured. Results Glutamine dose‐dependently amplified insulin secretion in the presence of high glucose in both MIN6‐K8 cells and Glud1 KOβCL. Inhibition of glutaminases, the enzymes that convert glutamine to glutamate, dramatically reduced the glutamine‐amplifying effect on insulin secretion. A substantial amount of glutamate was produced from glutamine through direct conversion by glutaminases. Glutamine also increased [Ca 2+ ] i at high glucose, which was abolished by inhibition of glutaminases. Glutamic acid dimethylester (dm‐Glu), a membrane permeable glutamate precursor that is converted to glutamate in cells, increased [Ca 2+ ] i as well as induced insulin secretion at high glucose. These effects of glutamine and dm‐Glu were dependent on calcium influx. Glutamine also induced insulin secretion in clonal β‐cells MIN6‐m14, which otherwise exhibit no insulin secretory response to glucose. Conclusions Glutamate converted from glutamine is an essential mediator that enhances calcium signaling in the glutamine‐amplifying effect on insulin secretion. Our data also suggest that glutamine exerts a permissive effect on glucose‐induced insulin secretion.